Epigenetic memory via concordant DNA methylation is inversely correlated to developmental potential of mammalian cells.
Epigenetic memory via concordant DNA methylation is inversely correlated to developmental potential of mammalian cells.
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DOI：
10.1371/journal.pgen.1007060
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发表时间：
2017-11
期刊：
影响因子：
4.5
通讯作者：
Laird CD
中科院分区：
文献类型：
--
作者：
Choi M;Genereux DP;Goodson J;Al-Azzawi H;Allain SQ;Simon N;Palasek S;Ware CB;Cavanaugh C;Miller DG;Johnson WC;Sinclair KD;Stöger R;Laird CD
在存储和传输表观遗传信息时，生物体必须平衡维持有关过去条件的信息的需要与对其当前和未来环境中的信息做出反应的能力。其中一些信息是由DNA甲基化编码的，它可以以可变的保真度从亲本链传递到子链。高保真度赋予个体DNA分子链之间强的模式匹配，从而在多轮DNA复制中模式稳定;较低的保真度赋予减少的模式匹配，从而更大的灵活性。在这里，我们提出了一个新的概念框架，一致性偏好比（RCP），它使用双链甲基化数据来量化系统的灵活性和稳定性，从而产生了一组给定的模式。我们发现分化的哺乳动物细胞具有高DNA甲基化稳定性，与早期报道一致。相比之下，培养物和胚胎中的干细胞的甲基化稳定性降低，但仍显着。我们的结论是，一致的DNA甲基化的偏好是一种一致的信息传递模式，从而提供了跨细胞分裂的表观遗传稳定性，即使在干细胞和那些经历发育转变。我们的RCP框架的更广泛的应用将允许比较表观遗传信息系统的细胞，发育阶段，和有机体的甲基化机制有很大的不同或尚未得到很好的理解。随着干细胞分化，它们获得了表观遗传标记，这些标记激活了一些基因并沉默了其他基因，最终产生了定义特定细胞谱系的特征。虽然现有的方法可以揭示给定细胞的分化状态或给定基因的活性状态，但没有一种方法可以沿着柔性和固定之间的表观遗传连续体沿着定位单个基因组区域。为了应对这一挑战，我们引入了一个新的框架来推断表观遗传稳定性的一致性的DNA甲基化模式的两条链的个别DNA分子。对于所有发育潜能的细胞，我们发现上链和下链甲基化模式的匹配比仅仅偶然的预期要频繁得多。随着细胞分化，模式转移的保真度增加，从而导致更高的表观遗传稳定性;去分化的特征在于稳定性下降。我们的指标有可能确定基因组区域，保持敏感的环境信号远远超出了谱系规范的间隔。
In storing and transmitting epigenetic information, organisms must balance the need to maintain information about past conditions with the capacity to respond to information in their current and future environments. Some of this information is encoded by DNA methylation, which can be transmitted with variable fidelity from parent to daughter strand. High fidelity confers strong pattern matching between the strands of individual DNA molecules and thus pattern stability over rounds of DNA replication; lower fidelity confers reduced pattern matching, and thus greater flexibility. Here, we present a new conceptual framework, Ratio of Concordance Preference (RCP), that uses double-stranded methylation data to quantify the flexibility and stability of the system that gave rise to a given set of patterns. We find that differentiated mammalian cells operate with high DNA methylation stability, consistent with earlier reports. Stem cells in culture and in embryos, in contrast, operate with reduced, albeit significant, methylation stability. We conclude that preference for concordant DNA methylation is a consistent mode of information transfer, and thus provides epigenetic stability across cell divisions, even in stem cells and those undergoing developmental transitions. Broader application of our RCP framework will permit comparison of epigenetic-information systems across cells, developmental stages, and organisms whose methylation machineries differ substantially or are not yet well understood. As stem cells differentiate, they acquire epigenetic marks that activate some genes and silence others, eventually producing the profiles that define specific cell lineages. While existing approaches can reveal the differentiation state of a given cell or the activity state of a given gene, none can locate an individual genomic region along the epigenetic continuum between flexible and fixed. To address this challenge, we introduce a new framework to infer epigenetic stability from the concordance of DNA methylation patterns on the two strands of individual DNA molecules. For cells of all developmental potentials, we find that top- and bottom-strand methylation patterns match far more often than expected by chance alone. As cells differentiate, the fidelity of pattern transfer increases, thereby resulting in higher epigenetic stability; dedifferentiation is characterized by declining stability. Our metric has the potential to identify genomic regions that remain sensitive to environmental signals well beyond the interval of lineage specification.
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影响因子：
3.7
作者：
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